NEURAL MECHANISMS OF CORTISOL SUPPRESSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To determine whether psychosocially induced suppression of cortisol in socially subordinate female marmosets is mediated, in part, by endocrine inhibition at the level of the brain or pituitary, as a model for understanding chronic endocrine dysregulation associated with a variety of human neuropsychiatric disorders. Hypocortisolism, or insufficient secretion of cortisol from the adrenal cortex, may occur in humans as a consequence of early or traumatic stress and may play a fole in the pathophysiology of numerous stress-related disorders; however, few animal models are available for investigation of the underlying mechanisms. Female common marmosets offer a promising primate model of stress-related hypocortisolism, as they undergo chronic reductions in circulating cortisol after becoming subordinate in a social group. In this study, we treated dominant and subordinate females with the cortisol synthesis inhibitor metyrapone and corticotropin-releasing factor (CRF), to characterize the effects of subordination on central regulation of the hypothalamic-pituitary-adrenal axis. Seven dominant and six subordinate females were treated with CRF, following pretreatment with metyrapone or water. Plasma adrenocorticotropin (ACTH) and cortisol concentrations were determined before metyrapone or water treatment, and, subsequently, after CRF treatment. Following metyrapone treatment, subordinates had similar cortisol levels to dominants, but significantly higher ACTH levels. During CRF challenges, cortisol concentrations were lower and ACTH concentrations higher in subordinates, although net integrated responses to CRF did not differ. Cortisol-to-ACTH ratios were consistently lower in subordinates. These results confirm previous findings of low cortisol concentrations and blunted adrenal responsiveness in subordinates, and suggest that when differences in cortisol levels are eliminated, subordinates exhibit exaggerated hypothalamic drive to the pituitary. These neuroendocrine alterations in subordinate marmosets resemble those in posttraumatic stress disorder patients and adult survivors of child abuse. This research used WNPRC Animal Services (marmoset colony) and Assay Services.